Principal Investigator: Kathleen Boris-Lawrie, PhD, The Ohio State University
All retroviruses encode a small, multifunctional genome that expresses a relatively large and complex proteome. Retroviruses have adopted specialized post-transcriptional control mechanisms to maximize their coding capacity, while economically maintaining the information stored in cis-acting replication sequences. In the initial 3 years of this PPG, results of proteomic, genetic and biochemical analysis of retrovirus genomes have identified a specialized post-transcriptional control mechanism operated by RNA helicase A (RHA) on selected retrovirus and cellular genes. Project 3 has shown that RHA specifically recognizes structural features of the 5' terminal post-transcriptional control element (PCE) and neutralizes complex features of the 5' untranslated region (UTR) to facilitate efficient cap-dependent translation initiation. Our results of biochemical analyses and genome-wide translation profiling have identified a subset of biologically-related genes that require RHA for their efficient translation and contain a complex 5' UTR with PCE activity. These genes are collectively designated the RHA regulon and represent growth control genes with established roles in cancer: junD; c-jun; junB; FOS, ARF-1; MET. Specifically, we postulate the RHA regulon is an inducible translational control mechanism of selected genes, whose dysregulation contributes to alterations of the cellular microenvironment leading to transformation and paraneoplastic disease.
A primary focus of this highly interactive Continuation is to understand the scope and regulation of the RHA/PCE translational control axis in retroviral and host genes. Three interrelated aims test fundamental aspects of our hypothesis and then apply that knowledge to investigate the overlay of RHA/PCE translational control with Arf-mediated osteoclast activity and Tax tumor growth. Our specific aims are to: 1) investigate essential features of RHA gene expression and cytoplasmic localization during cell cycle progression; 2) examine role of RHA translational activity in osteoclast activity and Tax tumor model; and 3) assess the structure/function of junD PCE in relation to the retrovirus PCE database.
Long-term objectives are application of knowledge of the RHA regulon to develop vectors and small molecules to selectively modulate RHA responsive genes involved in neoplastic transformation, paraneoplastic and retrovirus disease.